SUMMARY As the population grows older, the demand for improved methods to study cerebrovascular diseases has rapidly increased. At the same time, there has been burgeoning interest in reproducing physiological properties of blood- brain-barrier (BBB) in vitro that can be helpful in both basic and clinical studies. A need therefore exists for standardized models as tools to help scientists better understand the physiological and pathological mechanisms involved in cerebrovascular diseases, including Alzheimer?s disease (AD). The proposed studies are aimed at developing a versatile BBB model that recapitulates BBB microvascular networks (VNs) in a three dimensional (3D) microfluidic platform, and apply this model to AD pathogenesis research. Building on our extensive set of preliminary and related data, we propose to recreate 3D AD-BBB VNs within extracellular matrix (ECM) scaffolds that enable intercellular signaling and exposure to biochemical gradients in a well-defined microenvironment. AD is a progressive neurodegenerative disease which is characterized by deterioration of cognitive function and deposition of ?-amyloid (A?) peptides. We previously reported that human neural progenitor cells overexpressing Familial AD (FAD) mutations in the amyloid-? precursor protein (APP) and presenilin 1 (PSEN1) genes grown in a 3D culture system successfully recapitulate AD pathologies (3D AD culture model). However, this model lacks BBB components, which are critical to neurological function and AD pathogenesis. We will develop 3D- differentiated AD cells in a 3D microfluidic platform in the presence of the BBB VNs (3D AD-BBB VN model). We will investigate how the BBB is disrupted in AD and whether optimizing the BBB can ameliorate AD progression. Our 3D AD-BBB VN model will be useful for both BBB-related disease pathogenic cascades, such as AD, and drug discovery in a human brain-like environment.